Merkel cell polyomavirus (MCV) is a novel human polyomavirus that has recently been discovered in Merkel cell carcinoma (MCC), a highly lethal skin cancer. Excessive exposure to ultraviolet (UV) radiation and immunosuppression are the most important risk factors for MCV-associated cancers. MCC metastasizes rapidly. It is one of the most aggressive human skin cancers with an extremely high mortality rate of 33% exceeding the rate of melanoma and less than 45% five-year survival rate. The incidence of MCC has tripled over the past 20 years as the aging population with prolonged sun exposure increases. Although MCV is an abundant virus on human skin, many aspects of the viral life cycle remain poorly understood. It is also unclear how MCV infection changes skin physiology to cause the highly aggressive MCC. With the high prevalence of MCV infection and the increasing amount of MCC diagnosis, there is a need to better understand the virus and its oncogenic potential. Recently, we discovered that the host protein Brd4 interacts with the MCV large T antigen (LT) and recruits the cellular replication factor RFC to support viral DNA replication. Thi study provides the first insight into the MCV replication machinery. We further demonstrated that, during MCV infection, the virus activates and recruits host DNA damage response (DDR) factors to support viral DNA replication. In addition, the MCV LT C-terminal DNA binding and helicase region also causes DNA damage in the host genome to induce DDR and activate p53, leading to inhibition of cellular proliferation. Our study explains why deletion of the LT C-terminl region is a critical event during MCV-induced oncogenesis. Building on these new discoveries, we hypothesize that MCV hijacks the cellular DNA repair systems to aid its own replication and dysregulation of the conflicting interactions between the invading MCV genomes and the host DNA repair machinery can result in genomic instability and cancer. We will use a number of innovative techniques established in our lab to elucidate the MCV life cycle and host DNA repair in naturally infected cells, to determine the mechanisms by which host DDR factors contributes to MCV replication, and to investigate how sunlight exposure/UV radiation promotes MCV-induced oncogenic progression. Through these integrated studies, our goal is to provide greater understanding of the MCV life cycle and oncogenic mechanism, and offer promising leads for developing effective therapeutic strategies to cure MCV infection and associated cancers. These studies will be feasible, and will benefit greatly from our own expertise in MCV research as well as from the collaborations and resources for skin disease research that we have established in the UPENN community.